Deconstruction of human age-related cataract capsules defines aging

Age-related cataracts (ARC), a disease associated with aging, is the leading cause of blindness worldwide. In 2020, an estimated 94 million people older than 50 years were blind or visually impaired globally due to cataract. However, current treatment strategies remain unsatisfactory, primarily due to the complex and heterogeneous pathogenesis of ARC. To better understand the underlying mechanisms and identify potential therapeutic targets, we generate a comprehensive atlas of age-related cataracts at a single-cell resolution, encompassing three disease states—mild cataract group (Mild), severe cortical cataract group (Severe_C), and severe nuclear cataract group (Severe_N)—with a total of 230,838 lens epithelial cells (LECs) derived from the lens capsules of 554 patients. We found that ARC involves seven distinct lens capsule cell types, with notable differences in cellular composition and functional states across disease severities. Unexpectedly, we discovered that neuronal axonal ingrowth into the lens is associated with cataractogenesis and its progress. All three disease groups showed significant enrichment of the neurotrophic SLIT-ROBO signaling pathway, suggesting a conserved neurogenic involvement in ARC. Furthermore, Cluster 0 exhibited high expression of the neurotrophic factor NRG1, which forms a stable ligand-receptor axis with the ERBB3 receptor on sympathetic neurons. These findings not only reveal the heterogeneity of ARC at the levels of cellular composition and signaling pathways, but also suggest that neuro-lens interactions may play a critical role in cataract development. This provides a new perspective for understanding the pathogenesis of age-related cataracts and offers potential directions for the development of targeted therapies in the future.